Cigarette smoking is the leading cause of preventable death in the U.S. The vast majority of individuals who attempt to quit smoking will relapse within the initial two weeks of the cessation effort. Importantly, sustaining abstinence through those initial weeks is associated with a precipitous decrease in relapse risk. The overarching aim of this 1st revision of a competing continuation application is to continue a project focused on the development and application of a human-laboratory model for experimentally analyzing how an initial period of sustained smoking abstinence may reduce relapse risk. In this model, smokers are randomly assigned to conditions in which they earn monetary reinforcement contingent on achieving varying durations of smoking abstinence. Participants report to the laboratory daily for two weeks to verify smoking status, complete subject-rating forms, and participate in behavioral and other testing. Results from a series of experiments conducted during the prior funding period using this model suggest that an initial period of sustained abstinence may lower relapse risk by (1) decreasing nicotine withdrawal and craving, (2) decreasing expectations of positive and negative reinforcement from smoking, (3) decreasing the relative reinforcing effects of smoking and (4) increasing subjects'perceived ease of abstaining and confidence in their ability to abstain. In this revised application we propose to expand the scope of this model by including assessments of abstinence effects on cue reactivity, inhibitory responding, and associated brain activity using fMRI. Experiment 1 will be a thorough, parametric assessment of initial smoking abstinence effects on this expanded battery of behavioral, cognitive, and neurobiological functioning. Experiments 2 and 3 will use the model to examine how two efficacious pharmacotherapies for smoking cessation (nicotine replacement therapy and varenicline) enhance or otherwise alter the effects of an initial period of sustained abstinence. These medications are known to increase initial abstinence rates, but much remains to be learned about how they do so especially their effects on brain function. Overall, the proposed studies have the potential to contribute important new scientific knowledge regarding behavioral, cognitive, and neurobiological changes that occur during initial smoking abstinence that may directly reduce relapse risk. Such knowledge may provide insights into how to better target therapeutic interventions and in that manner help more people succeed in quitting smoking. PUBLIC HEALTH RELEVANCE: Cigarette smoking is the leading cause of preventable death in the U.S. Relapse patterns among those attempting to quit smoking suggest that those who are able to persevere through the initial two weeks of trying to quit have a strikingly improved chance of long-term success. This project is focused on experimentally analyzing behavioral, cognitive, and neurobiological changes that occur during those initial weeks of sustaining abstinence and elucidating how they may position a person for longer-term success.